The story of living in spite of melanoma, metastasis, vaccines, anti-PD-1, lung removal, and stereotactic radiation. The story of life with family and friends. {Posts under ~ Sew Chaotically, Travel Chaotically, and Chaotic Cookery also housed within! A girl's gotta have fun!}

About Me

Who am I? That is a question the rest of you could probably answer better than I. I am a wife, mother, daughter, sister, friend, pediatric nurse practitioner, cook, teacher, gardener, lover of words and music, occasional seamstress, and homemaker. I do have a couple of talents of questionable merit: I can create a decent meal in less than 30 minutes. I can feed and/or soothe almost any baby. And I can remember practically any song I've ever heard. For the rest, I'd rather those who know me decide.

Tuesday, April 4, 2017

Imiquimod and Mebendazole...drugs repurposed for mousie melanoma

Folks in melanoma world tend to go nuts when reports like these hit the news stand. Partly out of desperation for an effective treatment, but also because sometimes such reports fail to make it clear that these great strides were attained in mousies rather than ratties. Despite the skepticism my first sentence may convey, mice ARE the first step toward ratties and if they can find a treatment that works for more of my melanoma peeps, I'll take it!!!

First up is imiquimod, a cream that is usually used topically to treat venereal warts, basal cell carcinoma, and actinic keratosis. These little mice seem to have had it applied topically (??? I think) as well as having it injected in their tail veins (not sure which vein that would be in ratties!!!) followed by radiation and it seemed to make melanoma lesions more responsive to that treatment.

Next there's mebendazole, an old, cheap, oral drug most often used to treat pin worms in kids...but also infestations of many other wormy critters as well as giardia. Generally, it is safe to use, though in large doses can cause bone marrow suppression. As an aside, I had a good many doses of this as a child because my mother seemed to have been of the persuasion that an ounce of prevention was worth a pound of cure....not that this med works like that for worms nor melanoma, as I sit here today as a Stage IV melanoma rattie!!!

Toll-like
receptor (TLR) ligands are strongly considered immune-adjuvants for
cancer immunotherapy and have been shown to exert direct anti-cancer
effects. This study was performed to evaluate the synergistic
anti-cancer and anti-metastatic effects of the TLR7 agonist imiquimod
(IMQ) during radiotherapy for melanoma. The pretreatment of B16F10 or
B16F1 cells with IMQ combined with γ-ionizing radiation (IR) led to
enhanced cell death via autophagy, as demonstrated by increased
expression levels of autophagy-related genes, and an increased number
of autophagosomes in both cell lines. The results also confirmed that
the autophagy process was accelerated via the reactive oxygen species
(ROS)-mediated MAPK and NF-κB signaling pathway in the cells
pretreated with IMQ combined with IR. Mice subcutaneously injected
with melanoma cells showed a reduced tumor growth rate after
treatment with IMQ and IR. Treatment with 3-methyladenine (3-MA),
ameliorated the anti-cancer effect of IMQ combined with IR.
Additionally, the combination therapy enhanced anti-cancer immunity,
as demonstrated by an increased number of CD8+ T cells and decreased
numbers of regulatory T cells (Treg) and myeloid-derived suppressor
cells (MDSCs) in the tumor lesions. Moreover, the combination therapy
decreased the number of metastatic nodules in the lungs of mice that
were injected with B16F10 cells via the tail vein. In addition, the
combination therapy enhanced systemic anti-cancer immunity by
increasing the abundances of T cell populations expressing IFN-γ and
TNF-α. Therefore, these findings suggest that IMQ could serve as a
radiosensitizer and immune booster during radiotherapy for melanoma
patients.The repurposed anthelmintic
mebendazole in combination with trametinib suppresses refractory
NRASQ61K melanoma. Simulam-Rosenthal,
Dakshanamurthy, Gaur, et al. Oncotarget. 2017 Feb 2.

Structure-based drug
repositioning in addition to random chemical screening is now a
viable route to rapid drug development. Proteochemometric
computational methods coupled with kinase assays showed that
mebendazole (MBZ) binds and inhibits kinases important in cancer,
especially both BRAFWT and BRAFV600E. We find that MBZ synergizes
with the MEK inhibitor trametinib to inhibit growth of
BRAFWT-NRASQ61K melanoma cells in culture and in xenografts, and
markedly decreased MEK and ERK phosphorylation. Reverse Phase Protein
Array (RPPA) and immunoblot analyses show that both trametinib and
MBZ inhibit the MAPK pathway, and cluster analysis revealed a protein
cluster showing strong MBZ+trametinib - inhibited phosphorylation of
MEK and ERK within 10 minutes, and its direct and indirect downstream
targets related to stress response and translation, including ElK1
and RSKs within 30 minutes. Downstream ERK targets for cell cycle,
including cMYC, were down-regulated, consistent with S- phase
suppression by MBZ+trametinib, while apoptosis markers, including
cleaved caspase-3, cleaved PARP and a sub-G1 population, were all
increased with time. These data suggest that MBZ, a well-tolerated
off-patent approved drug, should be considered as a therapeutic
option in combination with trametinib, for patients with NRASQ61mut
or other non-V600E BRAF mutant melanomas.